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Stage III and localized stage IV breast cancer: Irradiation alone vs irradiation plus surgery
0360-3016~82/01003IMM3.00/0 CopynBhl C 1982 Pcrymm PressLtd
??Original Contribution STAGE III AND LOCALIZED STAGE IV BREAST CANCER: IRRADIATION ALONE VS IRRADIATION PLUS SURGERY JOHN BEDWINEK,
M.D.,*D. VENKATA
JEANNE-I-I-E Division of Radiation
LEE.
AND
PH.D.*
Oncology, Mallinckrodt
RAO,
M.D.,?CARLOS
BARBARA
M.D.*
PEREZ,
A.B.$
FINEBERG,
Institute of Radiology. 4511 Forest Park, Washington University. St. LOUIS.MO
One hundred forty-seven patients witb non-inflammatory, Stage III and IV breast cancer were treated with imdirtion alone (54 patients) or with a combination of irradiation and mastectomy (93 patients). In tbe T, category, tk ktcal failure rate was 45 % (51 II) for tk irradiation alone pntients vs 12 % (3/25) for tbe irradiation pIus surgery patieats; in the T, category these figures were 65 % (28/43) vs 13 % (9/W, respectivdy. Corresponding local failure rates by size of primary tumor were 50% (2/4) vs 15% (S/29) for tumors O-5 cm, 43% (9/21) vs 14% (6/45) for 5-8 cm tumors, and 75 % (22/29) vs 5 % (l/20) for tumors 28 cm. The rates of regional failure for the two trestment methods were compared according to N stage; they were 9% (2/23) for irradiition aIone v’s 11 C (8/76) for irradiation phrs surgery in the N,, category, and 58% (18/31) vs 18% (3/17), respectively, for the N,_, category. A analysis for patients with tumors greater than 5 cm treated with irndiition &me did not sbow a doserespome decrease in Iocal failure rate with increasiug total tomor dose over a range of 4000 to 7000 rad, suggestiag that doses in this range 8re too kw for these hrge tumors. Since a significant Lte compliation r8te has been reported with doses bipber than tbii patients witb non-inflammatory, but large (z-5 cm) tumors, should be treated with a combinatiom of surgery and irradiation wbeneva posslbk to achieve maximum local-regional control witb a mbaimum prob8bility of complic8tions. In 36 patients witb inll8mm8t0ry arctbe rates of local 8nd regional fake were 52 % (15/29) and 38 96 (11/29), respectively, for patients b-eated witb imdiatkm abne, and 14 % (l/7) and 29% (2/7), respectively, for patients receiving irradiitlon plus surgery. Since none of these differences were statistically significmt, one cannot conclude that surgery should necessarily pIay a role in the treatment of intlammatory urcinoma. Breast cancer, Treatment
of breast cancer, Primary
irradiation.
Some
INTRODUCI’IOK
In I943
Haagensen
and Stout”
established
guidelines
for
authors2,‘3.20 have Stage
rates when treated
the operability
of carcinoma
of the breast. They observed
regional
control
that
with
clinical
surgery
and irradiation
patients
advanced
certain
disease
were
surgery
and
concluded
treated
with
irradiation
suggests
that
cancer
(American
categorically that with
Joint
cure by any local modality. or a combination treatment
locally
provide
freedom of life.
treatment
and/or
from
Stage
alone.
be
localized
whether
surgery.
irradiation)
breast pres-
guidelines
local-regional
irradiation,
they
to
patients
disease for the
treated
ysis. though
for the local
of
Therefore,
all Stage
also retrospective,
the
111 and
together
as a
of patients
has
in terms
of
likelihood
of
these reports
are
receiving
surgery
for that treatment
local-regional
of
by irradiation
not only
that the patients
by irradiation
and local-
with a combination
this population
were selected
had less extensive
III
higher
were analyzed
recurrence.”
plus irradiation
of the local
111 and non-metastatic
even though
subject to the criticism
Stage
have
reports.
IV patients
been shown to be quite variable. survival,‘4.‘5.20 but also in terms
111 6t non-
is, therefore.
Stage
that
than when treated
In these retrospective
single group.
they are beyond
cancer should be based upon rates rather than survival rates.
*Assistant tlnstructor. $Professor
by
micrometastases
local and regional
of AJC’ Stage
IV breast
cure should
advanced
therefore.
For this reason.
locall)
evidence”.‘9.20
of the two. The purpose
(surgery
duration
control
Recent
Stage IV) have distant
metastatic
patients
Committee’
ent at the time of diagnosis.
of
beyond
such
alone.
patients
features
found
IV patients
non-metastatic
disease
because than
alone. The following attempts
to minimize
the analthe
influence of this selection process by comparing these two treatment methods according to separate subgroups, in
Stage
local-regional
which all patients of a given subgroup have roughly the same probability of local-regional failure. The patients
Professor
$Data Manager. Requests to: John Bedwinek, M.D. Accepted for publication 2 I August
and Director.
3/
198 1.
Radiation Oncology 0 Biology ??Physics
32
with no&inflammatory carcinoma were broken down into separate subgroups depending on the AJC T-stage. size of the primary tumor. and the .4JC N-stage. The patients with inflammatory carcinoma were analyzed separately as a single group. In addition to comparing surgery plus irradiation with irradition alone for these various subgroups, this report also examines the effect of dose on the local failure rate for those patients (both inllammatory and non-inflammatory) who were treated by irradiation alone. METHODS
AND MATERIALS
Patient material All breast cancer patients receiving definitive irradiation (with or without surgery) at the Division of Radiation Oncology, Mallinckrodt Institute of Radiology, between the years 1960 and 1975 were reviewed and retrospectively staged according to the 1978 American Joint Committee Staging System.’ This staging process was based on the tumor descriptions and diagrams in the radiotherapy and hospital records. One hundred eightythree patients were identified as having Stage III or localized Stage IV disease and were followed until death or for a minimum of five years. These patients constitute the basis of this report. Twenty-three of these patients had clear-cut clinical criteria’.” for inflammatory carcinoma but had no mention of dermal lymphatic involvement in their pathology reports. Four patients had dermal lymphatic involvement but no clinical criteria for inflammatory carcinoma, and nine patients had both clinical criteria and dermal lymphatic involvement. Since previous reports’,” have shown that dermal lymphatic involvement alone, clinical criteria alone, or a combination of the two all have an equally poor prognosis, all of these 36 patients were considered to have inflammatory carcinoma and were anlayzed separately from the remaining 147 patients with non-inflammatory carcinoma. Table 1 shows the T & N distribution of all I83 patients under study; the patients with inflammatory carcinoma are distinguished by parentheses.
Treatment Of the patients with non-inflammatory received both surgery and irradiation, treated with irradiation alone. Seventeen
Table
1. T and N distribution
carcinoma, 93 and 54 were of the patients
of all 183 patients
Tz
T,
T4
NO
I1
40 (12)
51 (12)
N, N:
2
3
12 2
35 (9) 14 (7)
47 (9) 21 (7)
N,
2
2
3
21 (8)
28 (8)
Total
4
5
28
T,
Patients with inflammatory
llO(36)
carcinoma
Total
147 (36)
are in parentheses.
January 19X?. Volume 8. Number
I
Table 2. Distribution of patients with non-inflammatory carcinoma by T Sr N group and by treatment method T,N,, X RT alone XRT plus radical or modified radical mastectomy XRT plus total mastectomy
T,N2.J
T,N,,
T,h?!-)
Total
3
8
‘0
23
54
I5
3
36
7
61
5
2
20
5
32
receiving combined therapy had preoperative irradiation followed by surgery, and the remaining 76 had surgery and postoperative irradiation. Surgery, when employed, was either a radical, a modified radical, or a total mastectomy. Table 2 shows the distribution of the patients with non-inflammatory carcinoma by integrated T 8c N group and by treatment method. Twenty-nine of the 36 patients with inflammatory carcinoma were treated with irradiation alone, and the remaining 7 with a combination of surgery and irradiation. Two of the seven patients receiving combined treatment had a modified radical mastectomy and postoperative irradiation, two had a total mastectomy and postoptwo had preoperative irradiation erative irradiation, followed by a modified radical mastectomy, and one had preoperative irradiation followed by a total mastectomy. Irradiation of the chest wall or intact breast was accomplished with parallel opposed tangential beams of Cobaltm or 4 MV photons. The tumor dose was calculated at the mid-plane of the tangential field separation and ranged from 4000 to 5000 rad over 4 to 5 I /2 weeks. Patients who were treated with irradiation alone usually received an additional 1500 to 2500 rad boost to the residual mass in the breast with reduced tangential photon beams or with an appositional I O-l 6 MV electron beam. The total tumor dose received by the mass in the breast in the patients treated by irradiation alone was 4000 to 5000 rad in I2 patients, 5000 to 6000 rad in 28 patients, 6000 to 7000 rad in 38 patients and 7000 rad in 5 patients. The supraclavicular and axillary areas were treated with a single anterior photon beam (Cobal?“’ or 4 MV x-rays) angled 15” laterally to exclude the spinal cord. The supraclavicular dose at a depth of 3 cm was 4000 to 5000 rad in 4 to 5 l/2 weeks. The axillary dose from this anterior portal was calculated at the midplane of the A-P diameter, and a small posterior portal was used to bring this midplane axillary dose up to 4000 to 5000 rad. Any palpable axillary disease in the patients treated with irradiation alone was boosted to an additional 1500 to 2500 rad through the posterior portal or with an appositional electron beam field. Palpable supraclavicular disease was boosted with a reduced photon beam field or with electrons of appropriate energy. The internal mammary lymph nodes were irradiated to 4000 to 5000 tad with an anterior 6 cm wide portal; the medial border of this field was in the patient’s midline and was usually angled Y laterally to exclude the spinal cord.
Stage I I I and localized Stage IV None of the patients chemotherapy.
in this series received
adjuvant
End points The end points used to compare patients treated by irradiation alone with those treated by irradiation plus surgery were local failure rate, regional failure rate, and distant metastasis rate. Local failure is defined as persistence or regrowth of tumor in the breast or on the chest wall, and regional failure is the persistence or regrowth of disease in the supraclavicular. axillary or internal mammary node regions. The patients with non-inflammatory carcinoma were analyzed according to T stage. size of the primary tumor, and N stage. The endpoint for the analysis by T stage and primary tumor size was the rate of the local failure, and for the analysis by N stage, the endpoint employed was the rate of regional failure. In addition, the incidence of distant metastasis was recorded for each T stage, tumor size, and N stage category. All 36 patients with inflammatory carcinoma were analyzed as a single group since the small number of these patients precluded a breakdown by tumor size or by N stage. For the analysis of these patients, all three endpoints, rate of local failure, rate of regional failure, and rate of distant metastasis were used. RESULTS Non-inJlammatory carcinoma Figure 1 shows a significantly higher rate of local failure in the irradiation alone patients, 61% than in those treated with surgery and irradiation, 13%. Likewise, the regional failure rate was 37% in the irradiation alone patients in contrast to only 12% in the combined therapy group. The incidence of distant metastasis, however, was essentially the same for both groups, 65% vs 68%.
Figure 2 compares the local failure rate for the two treatment groups broken down by T stage. In the T, category, the 45% rate of local failure in the irradiation alone patients was greater than the 12% rate in the patients receiving combined therapy, but, because of the small number of T, patients treated with irradiation alone, this difference was not quite statistically significant. In the T, category, however, the difference between the two treatment groups was significant: 65% for irradiation alone vs 13% for irradiation plus surgery. Within the T, category, the incidence of distant metastasis was the same for the two treatment groups, 64% (7/l 1) vs 68% (I 7/25). and the same was true in the T, category, 65% (28/43) vs 68% (46/68). Since the size of the primary tumor influences the rate of local failure as much as, if not more than, T stage,14 irradiation alone was compared to irradiation plus surgery according to primary tumor size (Figure 3). There were too few patients treated with irradiation alone in the O-5 cm category for the difference in the rate of local failure between the two treatment groups to be significant; however, the irradiation alone patients had a significantly greater local failure rate than the surgery plus irradiation patients for both the 5-8 cm category, 43% vs 14% and the r8 cm category, 76% vs 5%. In the O-5 cm category the distant failure rate was 25% (I /4) for irradiation alone patients vs 52% (15/29) for the irradiation plus surgery patients; however, since there were only four patients in the O-5 category treated with irradiation alone, this difference has very little meaning. There was no difference in the distant metastasis rate between the two treatment groups within the 5-8 cm category, 67% (14/21) vs 68% (30/44), or within the 28 cm category. 69% (20/29) vs 90% ( 18/20).
u
i XRT
100
54L_1
XRT ALONE
g3~SURGERY
2 3 z!
AND XRT
33
breast cancer 0 J. BEDWINEK er al.
ALONE
SURGERY
AND
XRT
80 65%
d 60 t
LOCAL P=.OOO 1
REGIONAL P=.OOO7
DISTANT
45%
MET.
P= 0.7
Fig. 1. Rates of local, regional, and distant failure in 147 patients with non-inflammatory carcinoma; irradiation alone vs irradiation plus surgery. The numerators for a given site (local, regional, or distant) are the total number of failures in that site whether these failures occurred alone or in conjunction with a failure(s) in one or both of the other two sites. P values are by Chi square analysis.
P= .07
P:
.OOOl
Fig. 2. Local failure rate by treatment method and by T stage. The numerators are the total number of local failures whether these failures occurred alone or in conjunction with a regional and/or distant failure(s). P values are by Chi square analysis.
34
Radiation Oncology 0
?? XRT
Biology0 Physics
SURGERYAND XRT
S-8cm
P: .39
P= .02
bcm P:
.OOOl
Fig. 3. Local failure rate by treatment method and by size of the primary tumor in the breast. The numerators are the total number of local failures whether these failures occurred alone or in conjunction with a regional and/or distant failure(s). P values are by Chi square analysis.
Figure 4 shows the incidence of regional failure with respect to treatment method and nodal stage. For N stages N,, and N,, the regional failure rate was essentially the same in the two treatment groups: 0% vs 7% for the N,, category and 13% vs 15% for the N, category. For the N, category, the regional failure rate of 45% in the irradiation alone group was higher than the 11% rate in the irradiation plus surgery group, but this difference was not statistically significant because of the small number of patients. Similarly, there was a difference in the N, category, 65% vs 25% but again, this was not statistically significant. If the Nz and the N, categories are combined, the difference between the two treatment groups, 58% (18/31) vs 18% (3/17), becomes significant at the .03
?? XRT
; 3 zg LL
100
I
level. There was no significant difference in the incidence of distant metastasis between the two treatment groups for any of the four N stage categories: 50 (4/8) vs 70% (30/43) for N,; 60% (9/15) vs 67% (22/23) for N,; 73% (8/l 1) vs 56% (59) for N,; and 70% (14/20) vs 75% (6/8) for N,.
ALONE
O-5cm
January 1982, Volume 8, Number
Injammatory carcinoma The rate of local failure for the 29 patients with inflammatory carcinoma treated with irradiation alone was 52% (15/29) compared to 14% (l/7) for those treated with surgery plus irradiation. This difference was not statistically significant. Likewise, the difference in the regional failure rate between the irradiation alone plus surgery patients, 38% (1 l/29). and the irradiation patients, 29% (2/7), was not significant. The rate of distant metastasis was essentially the same for the two treatment groups, 2 I /29 (72%) vs 6/7 (86%). Effect of total dose on the local failure rate Figure 5 charts the local failure rate for the combinated group of the 29 inflammatory patients and the 54 non-intlammatory patients who were treated by irradiation alone. The incidence of local failure was plotted as a function of total dose received by the primary tumor in the breast for each of the three different tumor size categories. With the exception of the six patients with tumors O-5 cm, the incidence of local failure did not decrease with increasing total tumor dose. ’ Complications Table 3 lists the complications for all patients according to treatment method. A complication was considered
SURGERY
AND
100
XRT
r ‘4/19(‘4),
65% 2/3(671
Nl
No
P:
.96
Fig. 4. Regional
failure
-78
N2 P= .23
O-5cm
5-8cm
4f?l(SO)
80
Pi
e----a
o--b
*-....a 2 8 cwl
ALONE
f-
-
.-e
-
N3 P= .13
rate by treatment method and by N stage. The regional failure rate for the combined N2 and N3 patients treated with irradiation alone (18/31) was significantly greater (P < .03) than the regional failure rate for the combined N2 and N3 patients treated with surgery plus irradiation (3/17). The numerators are the total number of regional failures whether these failures occurred alone or in conjunction with a local and/or distant failure(s). P values are by Chi square analysis. Of the N3, irradiation alone patients, 12 had arm edema + supraclavicular nodes and 8 had supraclavicular nodes only. Of the N3, irradiation plus surgery patients, 5 had arm edema only and 3 had supraclavicular nodes only.
I
01 4g-
-. _
I Ymm TOTAL
yx&
DOSE
I 7axJ
( Rod)
Fig. 5. Percent local failure as a function of total dose received by the primary tumor in the breast for all patients (29 with inflammatory carcinoma and 54 with non-inflammatory carcinoma) treated with irradiation alone. The patients were separated into three categories according to the size of the primary tumor. The numerators at each point are the total number of local failures for a given size and dose whether these failures occurred alone or in conjunction with a regional and/or distant failure(s).
Stage III and localized Stage Table 3. Complications (inflammatory XRT alone (83 pts)
Moderate Breast fibrosis Breast edema Arm edema Stiff shoulder Brachial plexus injury
IV
and non-inflammatory) Surgery plus XRT ( 100 pts)
Severe
Moderate
Severe
12 2 5 1
4 0 0 0
0 0 10 2
0 0 3. I
1
0
0
I
to be moderate if it was clinically obvious but interfered only minimally with normal daily activities. A severe complication was one that markedly impaired normal daily function, was definitely distressing to the patient, or required some form of treatment. The most frequent complication, either moderate or severe, in the irradiation alone group was breast fibrosis, occurring in 19% of the patients; in the irradiation plus surgery group, arm edema, occurring in 13% of the patients, was the most common complication. DISCUSSION Non-inflammatory
carcinoma
The major problem with any retrospective comparison of surgery plus irradiatjon with irradiation alone in noninflammatory, AJC Stage III and Stage IV (localized) breast cancer is that patients receiving surgery and irradiation tend to be prognostically more favorable than those treated with irradiation alone. The current analysis reduced (but probably did not eliminate) the effect of this selection process by comparing the two treatment methods within separate prognostic subgroups. Within each T stage and tumor size subgroup, patients treated with irradiation plus surgery had a markedly lower incidence of local failure than those receiving irradiation alone. The two subgroups in which this difference was not statistically significant were the T, stage category and the O-5 cm size category, both of which contained an extremely small number of patients treated with irradiation alone. The regional failure rate was the same for the two treatment groups in the No and N, categories, but it was significantly lower for the irradiation plus surgery patients in the combined Nz and N, category. These results speak strongly for the use of combined therapy whenever possible in non-inflammatory Stage III and Stage IV breast cancer. The high local failure rate in the irradiation alone patients in this series is not unexpected in view of the fact that the total dose to the primary tumor in these patients was only in the range of 4000-7000 rad. It has been suggested that control of tumors greater than 5 cm can be obtained only with doses in the range of 8000 to 10,000 rad.‘.‘* The dose-response analysis in this study (Figure 4) supports this notion, since there was no decrease in the rate of local failure with increasing dose over the range of
breast cancer 0
J. BEDWINEK et 01.
35
4000
to 7000 rad in those patients with primary tumors greater than 5 cm. The necessity for doses of 800010,000 rad in patients with these large (~5 cm) tumors is further confirmed when one compares other series of locally advanced breast cancer patients treated to 7000 rad or less2~‘3*‘s~20 with series in which the total tumor dose was 8000-l 0,000 rad. 5*q~‘ The 8 local-regional failure rate in the former group of reports2.“.‘5*20was 40-60%, which is in sharp contrast to the 15-25% incidence of localregional failure in the high dose reports.‘.‘*‘* In two of these latter reports,‘*‘* the high doses were achieved by an interstitial implant. The 15-25% local-regional failure rate in the reports using 8000 to 10,000 rad is comparable to the 12% local failure rate and 1 1% regional failure rate seen in the present series of patients treated with a combination of surgery and irradiation to 5000 rad. It would appear that acceptably low rates of local-regional failure can be achieved only by high doses of irradiation (8000 to 10,000 rad) or by the combination of irradiation to 5000 rad and mastectomy. Although adequate tumor control for large breast cancers can be achieved with 8000 to 10,000 rad, the complication rate with these high doses may be considerable. Spanos et af.” found a 26% overall incidence of necrosis and severe fibrosis in patients receiving total tumor doses in excess of 8000 rad. The report of Spanos et al. is unique, for it is the only series using these high doses in which enough patients (30) were alive at eight years or more to yield a long-term complicaton rate. It is anticipated that, if all patients had survived, the overall serious complication rate would have been much higher. Because of the teachings of Haagensen and Stout,” surgeons (and radiotherapists) tend to relegate the local treatment of patients with non-inflammatory, locally advanced breast cancer to irradiaton alone. The results of the current analysis and others,2,‘3*‘s~‘7+” suggest that these patients are best served when the local therapy is a judicious combination of both irradiation and surgery whenever technically and medically feasible. Frequently, the local disease is fixed to the chest wall or is so massive that surgery is not possible. In these situations, two to three cycles of chemotherapy followed by irradiation to 4500 to 5000 rad may render the disease resectable. If, after chemotherapy and 5000 rad of radiotherapy, the gross disease is still not resectable, then it must be boosted up to 8000 to 10,000 rad. In most cases this boost is best accomplished by an interstitial implant in which the dose to adjacent normal tissue is kept to a minimum. Inflammatory carcinoma
The local and regional failure rates in the inflammatory patients in the current series who were treated by irradiation alone are similar to those reported by other authors.4.6 Although the local failure rate for the seven inIIammatory patients treated by irradiation plus surgery was lower than that for the 29 inflammatory patients treated by irradiation alone, the number of patients
Radiation Oncology 0 Biology 0 Physics
36
receiving the combined therapy was too small for this difference to be statistically significant. Also, this finding is contrary to the report of Barker et ~1.~ in which patients with inflammatory carcinoma treated by simple mastectomy plus irradiation had a higher rate of local failure (53%) than those treated with irradiation alone (38%). For these reasons, the improved local failure rate in these seven irradiation-plus-surgery patients must not be construed to mean that surgery should necessarily play a role in the treatment of inflammatory carcinoma of the breast. Preoperative irradiation and chemotherapy followed by conservative surgery may, in fact, yield acceptably low local-regional failure rates for inflammatory carcinoma, but this fact has not yet been firmly established.
January 1981. Volume 8. Number I Distant
metastases
In the current analysis the rate of distant metastases within any subgroup studied was extremely high (approximately 70%) and was unaffected by the treatment method. This strengthens the conclusions of other authors’s.‘9,20 that patients with locally advanced breast cancer should be considered to have microscopic distant metastases present at the time of diagnosis. The only hope of decreasing the incidence of subsequent clinically overt distant metastases in these patients will be the development of an effective systemic regimen. Adjuvant chemotherapy for locally advanced breast cancer has been shown to delay the onset of overt distant metastases, but has not resulted in a decrease in their ultimate incidence.‘,‘6, .
REFERENCES 1. American Joint Committee: Manual for Staging 01 Cancer 1978. Chicago, Illinois. 1978. 2. Atkins, H.L., Horrigan, W.D.: Treatment of locally
advanced carcinoma of the breast with roentgen therapy and simple mastectomy. Am. J. Roentgenol. 85: 860-864, 1961.
3. Barker, J.L., Montague, E.D., Peters, L.J.: Clinical experience with irradiation of inflammatory carcinoma of the breast with and without elective chemotherapy. Cancer 45: 625-239,
1980.
4. Barker, J.L., Nelson, III, A.J., Montague, E.D.: Inflammatory carcinoma of the breast. Radiology 121: 173-176, 1976.
5. Bruckman. J.E., Harris, J.R., Levene, M.B., Chaffey, J.T., Hellman, S.: Results of treating stage III carcinoma of the breast by primary radiation therapy. Cancer 43: 985-993. 1979. 6. Chu, A.M., Wood, W.C., Doucette, J.A.: Inflammatory breast carcinoma treated by radical radiotherapy. Cancer 45: 2730-2737, 1980. 7. Droulias. C.A., Sewell, C.W., McSweeney, M.B., Powell, R.W.: Inflammatory carcinoma of the breast: A correlation of clinical, radiologic and pathologic findings. Ann. Surg. 184: 217-222, 1976. 8. Fletcher, C.H.: Textbook of Radiotherapy. 3rd edition. Philadelphia, Lea & Febiger, 1980. 9. Fletcher, G.H., Montague, E.D.: Radical irradiation of advanced breast cancer. Am. J. Roentgenol. 93: 573-584, 1965.
IO. Haagensen, C.D., Stout, A.P.: Carcinoma of the breast, I1 criteria of operability. Ann. Surg. 118: 859-870, 10321051,1943. II. Lucas, F.V., Perez-Mesa, C.: Inflammatory carcinoma of the breast. Cancer 41: 1595-1605, 1978.
12. Montague,
E.D.: Radiation management of advanced breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 4: 305307, 1978.
13. Pearlman,
N.W. Guerra, O., Fracchia, A.A.: Primary inoperable cancer of the breast. Surg. Gynecol. Obstet. 143:
909-9 13, 1976. 14. Rao, D.V., Bedwinek, J.M.. Perez, C.A, Lee. J., Fineberg,
B.: Prognostic indicators in stage III and localized stage IV breast cancer. Cancer (In press). 15. Rubens, R.D. Armitage, P., Winter, P.J., Tong, D.. Hayward, J.L.: Prognosis in inoperable stage 111carcinoma of the breast. Eur. J. Cower 13: 805-8 I 1. 1977. 16. Rubens, R.D., Sexton, S., Tong, D., Winter. P.J., Knight, R.K., Hayward, J.L.: Combined chemotherapy and radiotherapy for locally advanced breast cancer. Eur. J. Cancer 16: 351-356, 1980. 17. Spanos. W.J., Montague, E.D., Fletcher, G.H.: Late complications of radiation only for advanced breast cancer. lnt. J. Radiat. Oncol. Biol. Phys. 6: l473-!476, 1980. 18. Syed, A.M.N.,
Puthawala, A., Fleming, P.. Neblett, D., Gowdy, R., Sheikha, K., Geroge, F., Eads, D., McNamara, C.: Combination of external and interstitial irradiation in the primary management of breast carcinoma. Cancer 46: 1360-1365, 1980. Terz, J.J., Romero. C.A., Kay, S., Brown, P.W.. Wassum, 19. J., King, R., Lawrence, W.: Preoperative radiotherapy for stage 111 carcinoma of the breast. Surg. Gynecol. Obstet. 147: 497-502,
1978.
20. Zucali, R., Uslenghi, C.. Kenda, R., Bonadonna, G.: Natu-
ral history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cuncer 37: 1422-143 I, 1976.
??Original Contribution STAGE III AND LOCALIZED STAGE IV BREAST CANCER: IRRADIATION ALONE VS IRRADIATION PLUS SURGERY JOHN BEDWINEK,
M.D.,*D. VENKATA
JEANNE-I-I-E Division of Radiation
LEE.
AND
PH.D.*
Oncology, Mallinckrodt
RAO,
M.D.,?CARLOS
BARBARA
M.D.*
PEREZ,
A.B.$
FINEBERG,
Institute of Radiology. 4511 Forest Park, Washington University. St. LOUIS.MO
One hundred forty-seven patients witb non-inflammatory, Stage III and IV breast cancer were treated with imdirtion alone (54 patients) or with a combination of irradiation and mastectomy (93 patients). In tbe T, category, tk ktcal failure rate was 45 % (51 II) for tk irradiation alone pntients vs 12 % (3/25) for tbe irradiation pIus surgery patieats; in the T, category these figures were 65 % (28/43) vs 13 % (9/W, respectivdy. Corresponding local failure rates by size of primary tumor were 50% (2/4) vs 15% (S/29) for tumors O-5 cm, 43% (9/21) vs 14% (6/45) for 5-8 cm tumors, and 75 % (22/29) vs 5 % (l/20) for tumors 28 cm. The rates of regional failure for the two trestment methods were compared according to N stage; they were 9% (2/23) for irradiition aIone v’s 11 C (8/76) for irradiation phrs surgery in the N,, category, and 58% (18/31) vs 18% (3/17), respectively, for the N,_, category. A analysis for patients with tumors greater than 5 cm treated with irndiition &me did not sbow a doserespome decrease in Iocal failure rate with increasiug total tomor dose over a range of 4000 to 7000 rad, suggestiag that doses in this range 8re too kw for these hrge tumors. Since a significant Lte compliation r8te has been reported with doses bipber than tbii patients witb non-inflammatory, but large (z-5 cm) tumors, should be treated with a combinatiom of surgery and irradiation wbeneva posslbk to achieve maximum local-regional control witb a mbaimum prob8bility of complic8tions. In 36 patients witb inll8mm8t0ry arctbe rates of local 8nd regional fake were 52 % (15/29) and 38 96 (11/29), respectively, for patients b-eated witb imdiatkm abne, and 14 % (l/7) and 29% (2/7), respectively, for patients receiving irradiitlon plus surgery. Since none of these differences were statistically significmt, one cannot conclude that surgery should necessarily pIay a role in the treatment of intlammatory urcinoma. Breast cancer, Treatment
of breast cancer, Primary
irradiation.
Some
INTRODUCI’IOK
In I943
Haagensen
and Stout”
established
guidelines
for
authors2,‘3.20 have Stage
rates when treated
the operability
of carcinoma
of the breast. They observed
regional
control
that
with
clinical
surgery
and irradiation
patients
advanced
certain
disease
were
surgery
and
concluded
treated
with
irradiation
suggests
that
cancer
(American
categorically that with
Joint
cure by any local modality. or a combination treatment
locally
provide
freedom of life.
treatment
and/or
from
Stage
alone.
be
localized
whether
surgery.
irradiation)
breast pres-
guidelines
local-regional
irradiation,
they
to
patients
disease for the
treated
ysis. though
for the local
of
Therefore,
all Stage
also retrospective,
the
111 and
together
as a
of patients
has
in terms
of
likelihood
of
these reports
are
receiving
surgery
for that treatment
local-regional
of
by irradiation
not only
that the patients
by irradiation
and local-
with a combination
this population
were selected
had less extensive
III
higher
were analyzed
recurrence.”
plus irradiation
of the local
111 and non-metastatic
even though
subject to the criticism
Stage
have
reports.
IV patients
been shown to be quite variable. survival,‘4.‘5.20 but also in terms
111 6t non-
is, therefore.
Stage
that
than when treated
In these retrospective
single group.
they are beyond
cancer should be based upon rates rather than survival rates.
*Assistant tlnstructor. $Professor
by
micrometastases
local and regional
of AJC’ Stage
IV breast
cure should
advanced
therefore.
For this reason.
locall)
evidence”.‘9.20
of the two. The purpose
(surgery
duration
control
Recent
Stage IV) have distant
metastatic
patients
Committee’
ent at the time of diagnosis.
of
beyond
such
alone.
patients
features
found
IV patients
non-metastatic
disease
because than
alone. The following attempts
to minimize
the analthe
influence of this selection process by comparing these two treatment methods according to separate subgroups, in
Stage
local-regional
which all patients of a given subgroup have roughly the same probability of local-regional failure. The patients
Professor
$Data Manager. Requests to: John Bedwinek, M.D. Accepted for publication 2 I August
and Director.
3/
198 1.
Radiation Oncology 0 Biology ??Physics
32
with no&inflammatory carcinoma were broken down into separate subgroups depending on the AJC T-stage. size of the primary tumor. and the .4JC N-stage. The patients with inflammatory carcinoma were analyzed separately as a single group. In addition to comparing surgery plus irradiation with irradition alone for these various subgroups, this report also examines the effect of dose on the local failure rate for those patients (both inllammatory and non-inflammatory) who were treated by irradiation alone. METHODS
AND MATERIALS
Patient material All breast cancer patients receiving definitive irradiation (with or without surgery) at the Division of Radiation Oncology, Mallinckrodt Institute of Radiology, between the years 1960 and 1975 were reviewed and retrospectively staged according to the 1978 American Joint Committee Staging System.’ This staging process was based on the tumor descriptions and diagrams in the radiotherapy and hospital records. One hundred eightythree patients were identified as having Stage III or localized Stage IV disease and were followed until death or for a minimum of five years. These patients constitute the basis of this report. Twenty-three of these patients had clear-cut clinical criteria’.” for inflammatory carcinoma but had no mention of dermal lymphatic involvement in their pathology reports. Four patients had dermal lymphatic involvement but no clinical criteria for inflammatory carcinoma, and nine patients had both clinical criteria and dermal lymphatic involvement. Since previous reports’,” have shown that dermal lymphatic involvement alone, clinical criteria alone, or a combination of the two all have an equally poor prognosis, all of these 36 patients were considered to have inflammatory carcinoma and were anlayzed separately from the remaining 147 patients with non-inflammatory carcinoma. Table 1 shows the T & N distribution of all I83 patients under study; the patients with inflammatory carcinoma are distinguished by parentheses.
Treatment Of the patients with non-inflammatory received both surgery and irradiation, treated with irradiation alone. Seventeen
Table
1. T and N distribution
carcinoma, 93 and 54 were of the patients
of all 183 patients
Tz
T,
T4
NO
I1
40 (12)
51 (12)
N, N:
2
3
12 2
35 (9) 14 (7)
47 (9) 21 (7)
N,
2
2
3
21 (8)
28 (8)
Total
4
5
28
T,
Patients with inflammatory
llO(36)
carcinoma
Total
147 (36)
are in parentheses.
January 19X?. Volume 8. Number
I
Table 2. Distribution of patients with non-inflammatory carcinoma by T Sr N group and by treatment method T,N,, X RT alone XRT plus radical or modified radical mastectomy XRT plus total mastectomy
T,N2.J
T,N,,
T,h?!-)
Total
3
8
‘0
23
54
I5
3
36
7
61
5
2
20
5
32
receiving combined therapy had preoperative irradiation followed by surgery, and the remaining 76 had surgery and postoperative irradiation. Surgery, when employed, was either a radical, a modified radical, or a total mastectomy. Table 2 shows the distribution of the patients with non-inflammatory carcinoma by integrated T 8c N group and by treatment method. Twenty-nine of the 36 patients with inflammatory carcinoma were treated with irradiation alone, and the remaining 7 with a combination of surgery and irradiation. Two of the seven patients receiving combined treatment had a modified radical mastectomy and postoperative irradiation, two had a total mastectomy and postoptwo had preoperative irradiation erative irradiation, followed by a modified radical mastectomy, and one had preoperative irradiation followed by a total mastectomy. Irradiation of the chest wall or intact breast was accomplished with parallel opposed tangential beams of Cobaltm or 4 MV photons. The tumor dose was calculated at the mid-plane of the tangential field separation and ranged from 4000 to 5000 rad over 4 to 5 I /2 weeks. Patients who were treated with irradiation alone usually received an additional 1500 to 2500 rad boost to the residual mass in the breast with reduced tangential photon beams or with an appositional I O-l 6 MV electron beam. The total tumor dose received by the mass in the breast in the patients treated by irradiation alone was 4000 to 5000 rad in I2 patients, 5000 to 6000 rad in 28 patients, 6000 to 7000 rad in 38 patients and 7000 rad in 5 patients. The supraclavicular and axillary areas were treated with a single anterior photon beam (Cobal?“’ or 4 MV x-rays) angled 15” laterally to exclude the spinal cord. The supraclavicular dose at a depth of 3 cm was 4000 to 5000 rad in 4 to 5 l/2 weeks. The axillary dose from this anterior portal was calculated at the midplane of the A-P diameter, and a small posterior portal was used to bring this midplane axillary dose up to 4000 to 5000 rad. Any palpable axillary disease in the patients treated with irradiation alone was boosted to an additional 1500 to 2500 rad through the posterior portal or with an appositional electron beam field. Palpable supraclavicular disease was boosted with a reduced photon beam field or with electrons of appropriate energy. The internal mammary lymph nodes were irradiated to 4000 to 5000 tad with an anterior 6 cm wide portal; the medial border of this field was in the patient’s midline and was usually angled Y laterally to exclude the spinal cord.
Stage I I I and localized Stage IV None of the patients chemotherapy.
in this series received
adjuvant
End points The end points used to compare patients treated by irradiation alone with those treated by irradiation plus surgery were local failure rate, regional failure rate, and distant metastasis rate. Local failure is defined as persistence or regrowth of tumor in the breast or on the chest wall, and regional failure is the persistence or regrowth of disease in the supraclavicular. axillary or internal mammary node regions. The patients with non-inflammatory carcinoma were analyzed according to T stage. size of the primary tumor, and N stage. The endpoint for the analysis by T stage and primary tumor size was the rate of the local failure, and for the analysis by N stage, the endpoint employed was the rate of regional failure. In addition, the incidence of distant metastasis was recorded for each T stage, tumor size, and N stage category. All 36 patients with inflammatory carcinoma were analyzed as a single group since the small number of these patients precluded a breakdown by tumor size or by N stage. For the analysis of these patients, all three endpoints, rate of local failure, rate of regional failure, and rate of distant metastasis were used. RESULTS Non-inJlammatory carcinoma Figure 1 shows a significantly higher rate of local failure in the irradiation alone patients, 61% than in those treated with surgery and irradiation, 13%. Likewise, the regional failure rate was 37% in the irradiation alone patients in contrast to only 12% in the combined therapy group. The incidence of distant metastasis, however, was essentially the same for both groups, 65% vs 68%.
Figure 2 compares the local failure rate for the two treatment groups broken down by T stage. In the T, category, the 45% rate of local failure in the irradiation alone patients was greater than the 12% rate in the patients receiving combined therapy, but, because of the small number of T, patients treated with irradiation alone, this difference was not quite statistically significant. In the T, category, however, the difference between the two treatment groups was significant: 65% for irradiation alone vs 13% for irradiation plus surgery. Within the T, category, the incidence of distant metastasis was the same for the two treatment groups, 64% (7/l 1) vs 68% (I 7/25). and the same was true in the T, category, 65% (28/43) vs 68% (46/68). Since the size of the primary tumor influences the rate of local failure as much as, if not more than, T stage,14 irradiation alone was compared to irradiation plus surgery according to primary tumor size (Figure 3). There were too few patients treated with irradiation alone in the O-5 cm category for the difference in the rate of local failure between the two treatment groups to be significant; however, the irradiation alone patients had a significantly greater local failure rate than the surgery plus irradiation patients for both the 5-8 cm category, 43% vs 14% and the r8 cm category, 76% vs 5%. In the O-5 cm category the distant failure rate was 25% (I /4) for irradiation alone patients vs 52% (15/29) for the irradiation plus surgery patients; however, since there were only four patients in the O-5 category treated with irradiation alone, this difference has very little meaning. There was no difference in the distant metastasis rate between the two treatment groups within the 5-8 cm category, 67% (14/21) vs 68% (30/44), or within the 28 cm category. 69% (20/29) vs 90% ( 18/20).
u
i XRT
100
54L_1
XRT ALONE
g3~SURGERY
2 3 z!
AND XRT
33
breast cancer 0 J. BEDWINEK er al.
ALONE
SURGERY
AND
XRT
80 65%
d 60 t
LOCAL P=.OOO 1
REGIONAL P=.OOO7
DISTANT
45%
MET.
P= 0.7
Fig. 1. Rates of local, regional, and distant failure in 147 patients with non-inflammatory carcinoma; irradiation alone vs irradiation plus surgery. The numerators for a given site (local, regional, or distant) are the total number of failures in that site whether these failures occurred alone or in conjunction with a failure(s) in one or both of the other two sites. P values are by Chi square analysis.
P= .07
P:
.OOOl
Fig. 2. Local failure rate by treatment method and by T stage. The numerators are the total number of local failures whether these failures occurred alone or in conjunction with a regional and/or distant failure(s). P values are by Chi square analysis.
34
Radiation Oncology 0
?? XRT
Biology0 Physics
SURGERYAND XRT
S-8cm
P: .39
P= .02
bcm P:
.OOOl
Fig. 3. Local failure rate by treatment method and by size of the primary tumor in the breast. The numerators are the total number of local failures whether these failures occurred alone or in conjunction with a regional and/or distant failure(s). P values are by Chi square analysis.
Figure 4 shows the incidence of regional failure with respect to treatment method and nodal stage. For N stages N,, and N,, the regional failure rate was essentially the same in the two treatment groups: 0% vs 7% for the N,, category and 13% vs 15% for the N, category. For the N, category, the regional failure rate of 45% in the irradiation alone group was higher than the 11% rate in the irradiation plus surgery group, but this difference was not statistically significant because of the small number of patients. Similarly, there was a difference in the N, category, 65% vs 25% but again, this was not statistically significant. If the Nz and the N, categories are combined, the difference between the two treatment groups, 58% (18/31) vs 18% (3/17), becomes significant at the .03
?? XRT
; 3 zg LL
100
I
level. There was no significant difference in the incidence of distant metastasis between the two treatment groups for any of the four N stage categories: 50 (4/8) vs 70% (30/43) for N,; 60% (9/15) vs 67% (22/23) for N,; 73% (8/l 1) vs 56% (59) for N,; and 70% (14/20) vs 75% (6/8) for N,.
ALONE
O-5cm
January 1982, Volume 8, Number
Injammatory carcinoma The rate of local failure for the 29 patients with inflammatory carcinoma treated with irradiation alone was 52% (15/29) compared to 14% (l/7) for those treated with surgery plus irradiation. This difference was not statistically significant. Likewise, the difference in the regional failure rate between the irradiation alone plus surgery patients, 38% (1 l/29). and the irradiation patients, 29% (2/7), was not significant. The rate of distant metastasis was essentially the same for the two treatment groups, 2 I /29 (72%) vs 6/7 (86%). Effect of total dose on the local failure rate Figure 5 charts the local failure rate for the combinated group of the 29 inflammatory patients and the 54 non-intlammatory patients who were treated by irradiation alone. The incidence of local failure was plotted as a function of total dose received by the primary tumor in the breast for each of the three different tumor size categories. With the exception of the six patients with tumors O-5 cm, the incidence of local failure did not decrease with increasing total tumor dose. ’ Complications Table 3 lists the complications for all patients according to treatment method. A complication was considered
SURGERY
AND
100
XRT
r ‘4/19(‘4),
65% 2/3(671
Nl
No
P:
.96
Fig. 4. Regional
failure
-78
N2 P= .23
O-5cm
5-8cm
4f?l(SO)
80
Pi
e----a
o--b
*-....a 2 8 cwl
ALONE
f-
-
.-e
-
N3 P= .13
rate by treatment method and by N stage. The regional failure rate for the combined N2 and N3 patients treated with irradiation alone (18/31) was significantly greater (P < .03) than the regional failure rate for the combined N2 and N3 patients treated with surgery plus irradiation (3/17). The numerators are the total number of regional failures whether these failures occurred alone or in conjunction with a local and/or distant failure(s). P values are by Chi square analysis. Of the N3, irradiation alone patients, 12 had arm edema + supraclavicular nodes and 8 had supraclavicular nodes only. Of the N3, irradiation plus surgery patients, 5 had arm edema only and 3 had supraclavicular nodes only.
I
01 4g-
-. _
I Ymm TOTAL
yx&
DOSE
I 7axJ
( Rod)
Fig. 5. Percent local failure as a function of total dose received by the primary tumor in the breast for all patients (29 with inflammatory carcinoma and 54 with non-inflammatory carcinoma) treated with irradiation alone. The patients were separated into three categories according to the size of the primary tumor. The numerators at each point are the total number of local failures for a given size and dose whether these failures occurred alone or in conjunction with a regional and/or distant failure(s).
Stage III and localized Stage Table 3. Complications (inflammatory XRT alone (83 pts)
Moderate Breast fibrosis Breast edema Arm edema Stiff shoulder Brachial plexus injury
IV
and non-inflammatory) Surgery plus XRT ( 100 pts)
Severe
Moderate
Severe
12 2 5 1
4 0 0 0
0 0 10 2
0 0 3. I
1
0
0
I
to be moderate if it was clinically obvious but interfered only minimally with normal daily activities. A severe complication was one that markedly impaired normal daily function, was definitely distressing to the patient, or required some form of treatment. The most frequent complication, either moderate or severe, in the irradiation alone group was breast fibrosis, occurring in 19% of the patients; in the irradiation plus surgery group, arm edema, occurring in 13% of the patients, was the most common complication. DISCUSSION Non-inflammatory
carcinoma
The major problem with any retrospective comparison of surgery plus irradiatjon with irradiation alone in noninflammatory, AJC Stage III and Stage IV (localized) breast cancer is that patients receiving surgery and irradiation tend to be prognostically more favorable than those treated with irradiation alone. The current analysis reduced (but probably did not eliminate) the effect of this selection process by comparing the two treatment methods within separate prognostic subgroups. Within each T stage and tumor size subgroup, patients treated with irradiation plus surgery had a markedly lower incidence of local failure than those receiving irradiation alone. The two subgroups in which this difference was not statistically significant were the T, stage category and the O-5 cm size category, both of which contained an extremely small number of patients treated with irradiation alone. The regional failure rate was the same for the two treatment groups in the No and N, categories, but it was significantly lower for the irradiation plus surgery patients in the combined Nz and N, category. These results speak strongly for the use of combined therapy whenever possible in non-inflammatory Stage III and Stage IV breast cancer. The high local failure rate in the irradiation alone patients in this series is not unexpected in view of the fact that the total dose to the primary tumor in these patients was only in the range of 4000-7000 rad. It has been suggested that control of tumors greater than 5 cm can be obtained only with doses in the range of 8000 to 10,000 rad.‘.‘* The dose-response analysis in this study (Figure 4) supports this notion, since there was no decrease in the rate of local failure with increasing dose over the range of
breast cancer 0
J. BEDWINEK et 01.
35
4000
to 7000 rad in those patients with primary tumors greater than 5 cm. The necessity for doses of 800010,000 rad in patients with these large (~5 cm) tumors is further confirmed when one compares other series of locally advanced breast cancer patients treated to 7000 rad or less2~‘3*‘s~20 with series in which the total tumor dose was 8000-l 0,000 rad. 5*q~‘ The 8 local-regional failure rate in the former group of reports2.“.‘5*20was 40-60%, which is in sharp contrast to the 15-25% incidence of localregional failure in the high dose reports.‘.‘*‘* In two of these latter reports,‘*‘* the high doses were achieved by an interstitial implant. The 15-25% local-regional failure rate in the reports using 8000 to 10,000 rad is comparable to the 12% local failure rate and 1 1% regional failure rate seen in the present series of patients treated with a combination of surgery and irradiation to 5000 rad. It would appear that acceptably low rates of local-regional failure can be achieved only by high doses of irradiation (8000 to 10,000 rad) or by the combination of irradiation to 5000 rad and mastectomy. Although adequate tumor control for large breast cancers can be achieved with 8000 to 10,000 rad, the complication rate with these high doses may be considerable. Spanos et af.” found a 26% overall incidence of necrosis and severe fibrosis in patients receiving total tumor doses in excess of 8000 rad. The report of Spanos et al. is unique, for it is the only series using these high doses in which enough patients (30) were alive at eight years or more to yield a long-term complicaton rate. It is anticipated that, if all patients had survived, the overall serious complication rate would have been much higher. Because of the teachings of Haagensen and Stout,” surgeons (and radiotherapists) tend to relegate the local treatment of patients with non-inflammatory, locally advanced breast cancer to irradiaton alone. The results of the current analysis and others,2,‘3*‘s~‘7+” suggest that these patients are best served when the local therapy is a judicious combination of both irradiation and surgery whenever technically and medically feasible. Frequently, the local disease is fixed to the chest wall or is so massive that surgery is not possible. In these situations, two to three cycles of chemotherapy followed by irradiation to 4500 to 5000 rad may render the disease resectable. If, after chemotherapy and 5000 rad of radiotherapy, the gross disease is still not resectable, then it must be boosted up to 8000 to 10,000 rad. In most cases this boost is best accomplished by an interstitial implant in which the dose to adjacent normal tissue is kept to a minimum. Inflammatory carcinoma
The local and regional failure rates in the inflammatory patients in the current series who were treated by irradiation alone are similar to those reported by other authors.4.6 Although the local failure rate for the seven inIIammatory patients treated by irradiation plus surgery was lower than that for the 29 inflammatory patients treated by irradiation alone, the number of patients
Radiation Oncology 0 Biology 0 Physics
36
receiving the combined therapy was too small for this difference to be statistically significant. Also, this finding is contrary to the report of Barker et ~1.~ in which patients with inflammatory carcinoma treated by simple mastectomy plus irradiation had a higher rate of local failure (53%) than those treated with irradiation alone (38%). For these reasons, the improved local failure rate in these seven irradiation-plus-surgery patients must not be construed to mean that surgery should necessarily play a role in the treatment of inflammatory carcinoma of the breast. Preoperative irradiation and chemotherapy followed by conservative surgery may, in fact, yield acceptably low local-regional failure rates for inflammatory carcinoma, but this fact has not yet been firmly established.
January 1981. Volume 8. Number I Distant
metastases
In the current analysis the rate of distant metastases within any subgroup studied was extremely high (approximately 70%) and was unaffected by the treatment method. This strengthens the conclusions of other authors’s.‘9,20 that patients with locally advanced breast cancer should be considered to have microscopic distant metastases present at the time of diagnosis. The only hope of decreasing the incidence of subsequent clinically overt distant metastases in these patients will be the development of an effective systemic regimen. Adjuvant chemotherapy for locally advanced breast cancer has been shown to delay the onset of overt distant metastases, but has not resulted in a decrease in their ultimate incidence.‘,‘6, .
REFERENCES 1. American Joint Committee: Manual for Staging 01 Cancer 1978. Chicago, Illinois. 1978. 2. Atkins, H.L., Horrigan, W.D.: Treatment of locally
advanced carcinoma of the breast with roentgen therapy and simple mastectomy. Am. J. Roentgenol. 85: 860-864, 1961.
3. Barker, J.L., Montague, E.D., Peters, L.J.: Clinical experience with irradiation of inflammatory carcinoma of the breast with and without elective chemotherapy. Cancer 45: 625-239,
1980.
4. Barker, J.L., Nelson, III, A.J., Montague, E.D.: Inflammatory carcinoma of the breast. Radiology 121: 173-176, 1976.
5. Bruckman. J.E., Harris, J.R., Levene, M.B., Chaffey, J.T., Hellman, S.: Results of treating stage III carcinoma of the breast by primary radiation therapy. Cancer 43: 985-993. 1979. 6. Chu, A.M., Wood, W.C., Doucette, J.A.: Inflammatory breast carcinoma treated by radical radiotherapy. Cancer 45: 2730-2737, 1980. 7. Droulias. C.A., Sewell, C.W., McSweeney, M.B., Powell, R.W.: Inflammatory carcinoma of the breast: A correlation of clinical, radiologic and pathologic findings. Ann. Surg. 184: 217-222, 1976. 8. Fletcher, C.H.: Textbook of Radiotherapy. 3rd edition. Philadelphia, Lea & Febiger, 1980. 9. Fletcher, G.H., Montague, E.D.: Radical irradiation of advanced breast cancer. Am. J. Roentgenol. 93: 573-584, 1965.
IO. Haagensen, C.D., Stout, A.P.: Carcinoma of the breast, I1 criteria of operability. Ann. Surg. 118: 859-870, 10321051,1943. II. Lucas, F.V., Perez-Mesa, C.: Inflammatory carcinoma of the breast. Cancer 41: 1595-1605, 1978.
12. Montague,
E.D.: Radiation management of advanced breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 4: 305307, 1978.
13. Pearlman,
N.W. Guerra, O., Fracchia, A.A.: Primary inoperable cancer of the breast. Surg. Gynecol. Obstet. 143:
909-9 13, 1976. 14. Rao, D.V., Bedwinek, J.M.. Perez, C.A, Lee. J., Fineberg,
B.: Prognostic indicators in stage III and localized stage IV breast cancer. Cancer (In press). 15. Rubens, R.D. Armitage, P., Winter, P.J., Tong, D.. Hayward, J.L.: Prognosis in inoperable stage 111carcinoma of the breast. Eur. J. Cower 13: 805-8 I 1. 1977. 16. Rubens, R.D., Sexton, S., Tong, D., Winter. P.J., Knight, R.K., Hayward, J.L.: Combined chemotherapy and radiotherapy for locally advanced breast cancer. Eur. J. Cancer 16: 351-356, 1980. 17. Spanos. W.J., Montague, E.D., Fletcher, G.H.: Late complications of radiation only for advanced breast cancer. lnt. J. Radiat. Oncol. Biol. Phys. 6: l473-!476, 1980. 18. Syed, A.M.N.,
Puthawala, A., Fleming, P.. Neblett, D., Gowdy, R., Sheikha, K., Geroge, F., Eads, D., McNamara, C.: Combination of external and interstitial irradiation in the primary management of breast carcinoma. Cancer 46: 1360-1365, 1980. Terz, J.J., Romero. C.A., Kay, S., Brown, P.W.. Wassum, 19. J., King, R., Lawrence, W.: Preoperative radiotherapy for stage 111 carcinoma of the breast. Surg. Gynecol. Obstet. 147: 497-502,
1978.
20. Zucali, R., Uslenghi, C.. Kenda, R., Bonadonna, G.: Natu-
ral history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cuncer 37: 1422-143 I, 1976.